This exploratory research project is designed to develop a novel multidisciplinary collaborative program of investigation and investigative training focused on the neuropathological consequences of severe and cerebral malaria in Thailand. This program will engage Thai physicians, scientists and other health professionals in basic and clinical studies of brain disorders resulting from malarial infection. Worldwide, the most important parasitic disease infecting the central nervous system of humans is Plasmodium falciparum malaria. Our project will take advantage of a unique convergence of resources and expertise at Mahidol University in Bangkok: (i) the Bangkok Hospital for Tropical Disease, Faculty of Tropical Medicine, a world-renowned malarial research facility, (ii) the Ramathibodi Hospital, Faculty of Medicine, Department of Radiology, fully equipped with a state-of-the-art Phillips Achieva 3.0 Tesla Magnetic Resonance system, and (iii) an established, decade-long collaborative relationship with investigators at Columbia University, now enhanced by a scientific linkage with the Hatch Magnetic Resonance Research Center. This investigation is designed to obtain preliminary prospective data to examine the hypothesis that axonal injury is responsible for neurological dysfunction in severe and cerebral malaria. We propose non-invasive high-field (3.0 Tesla) magnetic resonance (MR) studies to determine the extent of axonal injury in patients with cerebral malaria, in patients with other forms of severe and uncomplicated malaria, and in uninfected controls in Bangkok, Thailand. The proposed research has two specific aims: (1) to test the hypothesis that the degree of axonal injury will be greater in patients with cerebral malaria than in patients with other forms of severe malaria, as determined by MR imaging studies, including diffusion- weighted imaging (DWI) with the corresponding apparent diffusion coefficient (ADC) maps, diffusion tensor imaging (DTI) with correlating fractional anisotropy maps, and fluid attenuated inversion recovery (FLAIR) imaging;and (2) to test the hypothesis that the degree of axonal injury is greater in cerebral malaria than in other forms of severe malaria, as determined by quantitative proton (1H) MR spectroscopic measurements of lactate in brain ventricular fluid and of N-acetylaspartate, an indicator of axonal damage, in brain tissue. To our knowledge, these studies will be the first to examine patients with falciparum malaria using high-field (3.0 Tesla) MR. The results of this exploratory research project will provide the foundation for long-term research and training in the neuropathology of falciparum malaria and could suggest new neuroprotective strategies for the prevention of persistent neurological disorders that could be applied worldwide. PUBLIC HEALTH RELEVANCE: The research proposed in this application provides a systematic and logical approach to determining the role of axonal injury in the pathogenesis of neurological dysfunction in cerebral malaria. Our project takes advantage of the research opportunity created by the availability of a state-of-the-art high-field (3.0 Tesla) magnetic resonance instrument immediately adjacent to a world-class institution dedicated to the study of malaria. The proposed research project will provide a near ideal opportunity for the involvement and training of Thai physicians and scientists in an investigative project that is designed to lead to the development of new neuroprotective strategies that could be applied worldwide for the prevention of lifelong neurological disorders resulting from severe malaria. We have not yet determined the optimal neuroprotective intervention for future study in an R01 trial but are examining (i) an antibody-based therapy using a novel approach for antibody production developed at Columbia, (ii) a thiol antioxidant that crosses the blood brain barrier, N-acetyl cysteine amide, building on our earlier clinical studies with N-acetyl cysteine, and (iii) targeted desferrithiocin iron chelators that cross the blood brain barrier, extending our previous trials with the iron chelators, desferrioxamine, and deferiprone.